A variant of the <i>LRP4</i> gene affects the risk of chronic lymphocytic leukaemia transformation to Richter syndrome

Rasi, Silvia; Spina, Valeria; Bruscaggin, Alessio; Vaisitti, Tiziana; Tripodo, Claudio; Forconi, Francesco; Paoli, Lorenzo De; Fangazio, Marco; Sozzi, Elisa; Cencini, Emanuele; Laurenti, Luca; Marasca, Roberto; Visco, Carlo; Xu-Monette, Zijun Y.; Gattei, Valter; Young, Ken H.; Malavasi, Fabio; Deaglio, Silvia; Gaïdano, Gianluca; Rossi, Davide

doi:10.1111/j.1365-2141.2010.08482.x

Cited by 25 publications

(34 citation statements)

References 47 publications

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“…Limb muscle strength was measured using an SR-1 hanging scale (American Weigh Scales) as described previously (Shen et al, 2013). Briefly, forelimbs were allowed to grip a square metal grid that was connected to a hanging scale.…”

Section: Methodsmentioning

confidence: 99%

“…Recording was performed as described previously (Wu et al, 2012a, b;Shen et al, 2013). Briefly, mice were anesthetized with ketamine and xylazine (80 mg/kg and 20 mg/kg i.p., respectively).…”

Section: Methodsmentioning

confidence: 99%

“…Microelectrodes, 20 -40 MW when filled with 3 M KCl, were pierced into the center of muscle fibers (Wu et al, 2012a, b;Shen et al, 2013). Resting membrane potentials (Ϫ65 to Ϫ75 mV) remained stable during the experiment.…”

Section: Methodsmentioning

confidence: 99%

“…Mice lacking agrin do not form NMJ, but form primitive aneural AChR clusters that are thought to be involved in nerve-induced AChR clusters (Gautam et al, 1996;. Agrin is enriched at the synaptic basal lamina (SBL) between presynaptic and postsynaptic membranes (Ruegg et al, 1992;Jones et al, 1997;Burgess et al, 1999Eusebio et al, 2003;Bolliger et al, 2010) and remains at the NMJ for weeks after nerve degeneration. MuSK is a receptor tyrosine kinase that is essential for agrininduced clustering and for NMJ formation in vivo (DeChiara et al, 1996;Glass et al, 1996;Kim et al, 2008;.…”

Section: Introductionmentioning

confidence: 99%

“…CMS patients could possess mutations in genes in agrin signaling, including agrin itself, LRP4, MuSK, or rapsyn, a cytoskeletal protein that interacts with AChR Hamuro et al, 2008;Maselli et al, 2010Maselli et al, , 2012Ben Ammar et al, 2013;Ohkawara et al, 2014). On the other hand, MG patients could develop antibodies against agrin, MuSK, and/or LRP4 that are pathogenic (Hoch et al, 2001;Punga et al, 2011;Pevzner et al, 2012;Huijbers et al, 2013;Shen et al, 2013). These observations suggest that NMJ maintenance or function in adulthood may require agrin-LRP4-MuSK signaling.…”

Section: Introductionmentioning

confidence: 99%

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LRP4 Is Critical for Neuromuscular Junction Maintenance

et al. 2014

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The neuromuscular junction (NMJ) is a synapse between motor neurons and skeletal muscle fibers, and is critical for control of muscle contraction. Its formation requires neuronal agrin that acts by binding to LRP4 to stimulate MuSK. Mutations have been identified in agrin, MuSK, and LRP4 in patients with congenital myasthenic syndrome, and patients with myasthenia gravis develop antibodies against agrin, LRP4, and MuSK. However, it remains unclear whether the agrin signaling pathway is critical for NMJ maintenance because null mutation of any of the three genes is perinatal lethal. In this study, we generated imKO mice, a mutant strain whose LRP4 gene can be deleted in muscles by doxycycline (Dox) treatment. Ablation of the LRP4 gene in adult muscle enabled studies of its role in NMJ maintenance. We demonstrate that Dox treatment of P30 mice reduced muscle strength and compound muscle action potentials. AChR clusters became fragmented with diminished junctional folds and synaptic vesicles. The amplitude and frequency of miniature endplate potentials were reduced, indicating impaired neuromuscular transmission and providing cellular mechanisms of adult LRP4 deficiency. We showed that LRP4 ablation led to the loss of synaptic agrin and the 90 kDa fragments, which occurred ahead of other prejunctional and postjunctional components, suggesting that LRP4 may regulate the stability of synaptic agrin. These observations demonstrate that LRP4 is essential for maintaining the structural and functional integrity of the NMJ and that loss of muscle LRP4 in adulthood alone is sufficient to cause myasthenic symptoms.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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LRP4 Is Critical for Neuromuscular Junction Maintenance

et al. 2014

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Histologic transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma

et al. 2016

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Although generally considered a clinically indolent neoplasm, CLL/SLL may undergo transformation to a clinically aggressive lymphoma. The most common form of transformation, to DLBCL, is also known as Richter syndrome. Transformation determines the course of the disease and is associated with unfavorable patient outcome. Precise detection of transformation and identification of predictive biomarkers and specific molecular pathways implicated in the pathobiology of transformation in CLL/SLL will enable personalized therapeutic approach and provide potential avenues for improving the clinical outcome of patients. In this review, we present an overview of the pathologic features, risk factors, and pathogenic mechanisms of CLL/ SLL transformation.

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Hodgkin lymphoma transformation of chronic lymphocytic leukemia—A real life data from the Polish Lymphoma Research Group

Drozd‐Sokołowska

Zaucha

Żółtak

et al. 2019

Hematological Oncology

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Richter transformation (RT) of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) to Hodgkin lymphoma (HL) is a rare and unexpected event in the course of the disease and data on this phenomenon is still limited. To better understand the clinical and histological characteristics and the outcomes of HL variant of RT (HvRS) the Polish Lymphoma Research Group performed a nationwide survey which identified 22 patients with histologically proven HvRS diagnosed between 2002 and 2016. There were 16 (73%) males. The median age at CLL/SLL and HvRS diagnosis was 59 (39‐77) and 64 (40‐77) years, respectively. The median interval between CLL/SLL and HvRS diagnosis was 38 months (range: 0‐187). All patients had an advanced stage HL, and majority, 17 (77%), presented with B symptoms. The predominant subtypes of HL were nodular sclerosis (12; 55%) and mixed cellularity (9; 41%). Eighteen patients received non‐palliative treatment, including 13 who received driamycin, bleomycin, vinblastine, and dacarbazine (ABVD) regimen first line. Objective response was: 50%, with 33% complete remissions (61% and 46% for ABVD, respectively). Median overall survival reached 13.3 months (95% CI, 3.7‐NA). The only adverse prognostic factor for survival was a higher number (≤1 versus ≥2) of prior lines of treatment given for CLL/SLL with HR 3.57 (95% CI, 1.16‐10.92). We conclude, HvRS harbors a poor prognosis, especially in patients heavily pretreated for CLL/SLL. Response to standard first‐line anti‐HL chemotherapy is unsatisfactory, and new agents should be tested to improve the outcome.

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A variant of the LRP4 gene affects the risk of chronic lymphocytic leukaemia transformation to Richter syndrome

Cited by 25 publications

References 47 publications

LRP4 Is Critical for Neuromuscular Junction Maintenance

LRP4 Is Critical for Neuromuscular Junction Maintenance

Histologic transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma

Hodgkin lymphoma transformation of chronic lymphocytic leukemia—A real life data from the Polish Lymphoma Research Group

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